Faulds, K. | Search bioRxiv

bioRxiv2025

Unprecedented Cytotoxicity of Transition Metal Metallacarboranes on Triple Negative Breast Cancer Cells and a Vertebrate Cancer Model

Metallacarboranes have long been the subject of attention in the context of medicinal chemistry because of their promising characteristics and unconventional interactions with biological entities. The metal centre has been shown to have a significant influence on the internalisation and cytotoxicity of compounds in human cell lines. Additionally, specific nanomolar concentrations of metallacarboranes have demonstrated toxic effects on MDA-MB-231 cells under in vitro and in vivo conditions. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/635527v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@116eb95org.highwire.dtl.DTLVardef@1c4a181org.highwire.dtl.DTLVardef@474c3forg.highwire.dtl.DTLVardef@dec88c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2021

THEM6-mediated lipid remodelling sustains stress resistance in cancer

Despite the clinical benefit of androgen-deprivation therapy (ADT), the majority of patients with advanced prostate cancer (PCa) ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we identified thioesterase superfamily member 6 (THEM6) as a marker of ADT resistance in PCa. In patients, THEM6 expression correlates with progressive disease and is associated with poor survival. THEM6 deletion reduces in vivo tumour growth and restores castration sensitivity in orthograft models of CRPC. Mechanistically, THEM6 is located at the endoplasmic reticulum (ER) membrane and controls lipid homeostasis by regulating intracellular levels of ether lipids. Consequently, THEM6 loss in CRPC cells significantly alters ER function, reducing de novo sterol biosynthesis and preventing lipid-mediated induction of ATF4. Finally, we show that THEM6 is required for the establishment of the MYC-induced stress response. Thus, similar to PCa, THEM6 loss significantly impairs tumorigenesis in the MYC-dependent subtype of triple negative breast cancer. Altogether, our results highlight THEM6 as a novel component of the treatment-induced stress response and a promising target for the treatment of CRPC and MYC-driven cancer.

cancer biology↗